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Discovering New Human DNA Repair Genes by Bioinformatics

利用生物信息学发现新的人类DNA修复基因

基本信息

批准号：
7233298
负责人：
ASHOK S BHAGWAT
金额：
$ 24.46万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-22 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The completion of the human genome sequence presents unprecedented opportunities and challenges to biologists. While the access to complete sequences of genes whose protein products are well known provides new opportunities for testing hypotheses, the availability of sequences of genes with no known function poses critical challenges. To develop a model for how to predict functions of uncharacterized genes using bioinformatics, we will search the human genome for new DNA repair genes and then confirm their identity by testing the putative repair proteins for the predicted biochemical activities. The R21 part of the proposal will use mainly homology based methods to search for potential human DNA glycosylases. These tools will include development of improved sequence profiles of glycosylase families and utilization of these profiles along with the structural information for threading analysis of the human proteome. The R33 part of the proposal will use non-homology based methods including identification of catalytic centers and an associative search for DNA glycosylases in other known DNA modifying enzymes. Additionally, two other classes of DNA repair enzymes will be included in our search. This work will be a collaboration between three research groups; one with expertise in the development bioinformatics tools, a second group with extensive experience in application of this software and the last group with expertise in the biochemistry of DNA repair enzymes. While the first two groups will establish the necessary computer hardware, develop new software and perform the analysis that will predict new DNA repair genes, the latter group will set-up the necessary biochemical tests for the putative repair enzymes, clone the corresponding cDNAs into Escherichia coli and test them for activity. This integrated prediction-validation approach should be superior to a purely bioinformatics or a purely biochemical approach and may serve as a paradigm for searching biochemical functions in genomes of all organisms.

描述（申请人提供）：人类基因组序列的完成给生物学家带来了前所未有的机遇和挑战。虽然获得其蛋白质产物是众所周知的基因的完整序列为检验假设提供了新的机会，但没有已知功能的基因序列的可用性构成了关键挑战。为了开发一个模型，如何预测功能的未知基因使用生物信息学，我们将搜索人类基因组中的新的DNA修复基因，然后通过测试推定的修复蛋白的预测的生化活性来确认它们的身份。该提案的R21部分将主要使用基于同源性的方法来搜索潜在的人类DNA糖基化酶。这些工具将包括开发糖基化酶家族的改进的序列谱和利用这些谱沿着结构信息用于人蛋白质组的穿线分析。该提案的R33部分将使用基于非同源性的方法，包括鉴定催化中心和在其他已知DNA修饰酶中关联搜索DNA糖基化酶。此外，另外两类DNA修复酶也将被纳入我们的研究范围。这项工作将是三个研究小组之间的合作;一个具有开发生物信息学工具的专业知识，第二个小组具有应用该软件的丰富经验，最后一个小组具有DNA修复酶生物化学的专业知识。前两个小组将建立必要的计算机硬件，开发新的软件，并进行预测新的DNA修复基因的分析，后一个小组将为假定的修复酶建立必要的生化测试，将相应的cDNA克隆到大肠杆菌中并测试它们的活性。这种集成的预测-验证方法应该是上级的一个纯粹的生物信息学或一个纯粹的生物化学的方法，并可能作为一个范例，在所有生物体的基因组中搜索生化功能。